Experiments have been outlined to approach the following problem: What are the molecular mechanisms regulating mRNA stability during differentiation of murine erythroleukemia cells? To address this problem we have developed a system in which: (1)\cells reach the terminal stages of differentiation, become enucleated and resemble normal reticulocytes; and (2)\the entry of cells to the terminal differentiation program can be synchronized and occurs within 30 minutes. As differentiation proceeds in this system, nonglobin mRNA is dramatically destabilized but globin mRNA remains stable. We will test two hypotheses to account for this phenomenon. (1)\The primary structure of mRNA changes during differentiation. This may occur via shifts in initiation or termination of transcription, via changes in processing machinery or via alterations in gene structure. (2)\Genes are transcriptionally "switched off" in a specific order. These coding for the most stable mRNAs are "switched off" first, while genes coding for less stable mRNA are "switched off" later. We also will analyze changes in protein composition of specific ribonuclear protein (RNP) complexes during differentiation and try to correlate them with the changes in mRNA stability and in mRNA structure. We hope that the understanding of molecular mechanisms regulating differential mRNA stability may not only provide insights into the basis of abnormal growth and cancer but will enable us in the future to manipulate gene expression and perhaps correct some types of genetic defects such as beta~ thalassemia.